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FDA Breakthrough Status for Abemaciclib

Panelists:Adam M. Brufsky, MD, PhD, University of Pittsburgh Cancer Institute;Carlos L. Arteaga, MD, Vanderbilt University;Kimberly L. Blackwell, MD, Duke University Medical Center;Joyce A. O’Shaughnessy, MD, Baylor Charles A. Sammons Cancer Center;Sunil Verma, MD, MSEd, FRCPC, University of Calgary
Published: Thursday, Jul 07, 2016


Transcript:

Adam M. Brufsky, MD, PhD:
So, this trial was phase II. I think it did not, if I’m not mistaken, meet its primary endpoint which was overall survival. Is that correct?

Sunil Verma, MD, MSEd, FRCPC: No, they were looking at response rate.

Adam M. Brufsky, MD, PhD: Response rate. That’s right, I’m sorry. It didn’t meet that.

Sunil Verma, MD, MSEd, FRCPC: Yes. They had a qualification of response rate, but it’s hard to have a primary endpoint defined in such a manner because they had a range of response rates. Overall, 20% of patients had a response. Duration of response was good. PFS (progression-free survival) looks good. This is an active agent.

Adam M. Brufsky, MD, PhD: So, you’re the FDA. You see these data. Now, you’ve given them an accelerated designation. What do you do with it at this point in time knowing that there are other trials? And maybe, Joyce, you can summarize what those trials were…There are other abemaciclib trials now coming down the pike. There’s abemaciclib plus letrozole, and abemaciclib plus fulvestrant.

Kimberly L. Blackwell, MD: And HER2 targeted agents.

Adam M. Brufsky, MD, PhD: And abemaciclib plus HER2-targeted agent. Hopefully some of those trials will announce in the next year I’m guessing, maybe MONARCH-2 for example. So, what do you do? I’m putting you on the spot.

Sunil Verma, MD, MSEd, FRCPC: It’s a tough one.

Carlos L. Arteaga, MD: The FDA has defined the requirements to achieve breakthrough designation, and a result like this would fit that eligibility.

Adam M. Brufsky, MD, PhD: Right, and I agree with you. I’m curious as to what the other panel members think.

Sunil Verma, MD, MSEd, FRCPC: The FDA discussant at the sessions, she was excellent, and they also recognize that there is some subjectivity that goes along with this. But I think to Kim’s point, to have a targeted drug, a single agent therapeutic intervention that is active in this setting has not been shown outside of hormone receptor-positive disease and outside of chemotherapy. So, I think they’ll have to evaluate that, and evaluate the fact that it didn’t quite meet their definition of an effective response criteria. I think that’s a discussion.

Joyce A. O’Shaughnessy, MD: But clinical benefit rate is so important, and we know that from a clinical standpoint having prolonged stable disease or a response is the same thing in terms of your overall outcome. Response is not the best measure in the endocrine therapy setting. And so if we go back to the accelerated approval of capecitabine back in 1998, there was a 19% response rate. Clinical benefit rate wasn’t really on the radar screen, survival of 12.8 months. It met that unmet medical need, and I guess that’s the debatable point here. I think it’s an unmet need, and I really want the drug so I’m hoping that it will get approval.

Adam M. Brufsky, MD, PhD: I hope so, too. Apparently, they have an expanded access program that’s starting very soon anyway, but, nonetheless, hopefully it will be approved at some point.

Joyce A. O’Shaughnessy, MD: That’s good.

Kimberly L. Blackwell, MD: I think the real strength from a regulatory perspective is it’s not like this is the only study we’re going to have with this drug. We saw this with pertuzumab in particular, where larger registration randomized studies have been completed, and so they granted a conditional approval. I would hope that that would be the case here. We all know expanded access is valuable to patients, but it would be better I think just to have the drug while we’re waiting for the other studies to report out.

Adam M. Brufsky, MD, PhD: Going back, there’s a third one out now. There’s ribociclib, which actually has a whole series of trials that will announce. Any thoughts on ribociclib? Sunil?

Sunil Verma, MD, MSEd, FRCPC: The MONALEESA series of trials covers the ribociclib spectrum. MONALEESA-2 has met its primary endpoint of PFS, so this is going to be reported later this year. I think we are seeing this class effect now with palbociclib, now ribociclib being positive, and abemaciclib, which has a unique mode of action compared to the other two. So, this is an exciting time in hormone receptor-positive breast cancer. I think Kim mentioned we’re near doubling, to go from 14 months to 25 months PFS in the first-line setting. It is shifting things dramatically, and I think it really remains to be seen how we can take this and identify those patients early on to potentially potentiate this effect in the adjuvant setting, in the neoadjuvant setting. I think those are the kind of questions that we need to start discussing now.

Carlos L. Arteaga, MD: The fact that the control arm had such prolonged PFS suggests that this happened in a population that is very hormone dependent, very endocrine sensitive, and probably suggests that we should consider this in all patients in first-line in the metastatic setting and not wait.

Sunil Verma, MD, MSEd, FRCPC: What is the role of single-agent endocrine therapy now? Where does single-agent endocrine therapy?

Adam M. Brufsky, MD, PhD: Let’s get to that now. So, we have FALCON which has not—at least at the time of our discussion here—formally been announced but apparently there was a press release suggesting that it had a survival advantage as single agent.

Sunil Verma, MD, MSEd, FRCPC: PFS.

Adam M. Brufsky, MD, PhD: PFS advantage. Where do we put that now? Where do we put single-agent endocrine therapy?

Joyce A. O’Shaughnessy, MD: FALCON is the frontline study of fulvestrant versus anastrozole. It is following up on the first trial. Again, the thing about those patients—this is really the crux of the matter I think—is that they are totally endocrine therapy naïve, and that’s where I struggle. I will tell you that I agree with you, that the PALOMA-2 trial with the 14.5 months median PFS in the control arm says it’s an endocrine therapy–sensitive patient population. But, for these de novo metastatics that present with a very, very minor amount of bone disease, for example, we’ll have to wait for the FALCON actual results to see. I’m not yet convinced that every single patient who is first-line metastatic requires palbociclib. I’m one of those that still wants to see. Now, in PALOMA-1, when you looked at the de novo metastatics and the bone-onlys—bone-only disease—they got every bit as much benefit from the palbociclib. I couldn’t find a subset in that group that didn’t, including the most endocrine therapy sensitive patients. But still I have patients in the practice that have been on—we all do—first-line endocrine therapy for de novo metastatic disease for 5 plus years. There are these patients, and I think that we need to see, we have to wait for the FALCON data. We want to see some biomarker data. We want to really get deep into the clinical subsets on the PALOMA-2 data and then go from there because I think it’s still an open question.

Adam M. Brufsky, MD, PhD: Based on PALOMA-3, would you use palbociclib with fulvestrant?

Kimberly L. Blackwell, MD: Well, I would. I think Joyce and I are probably saying the same thing. I think we’ve learned from other targeted therapy experiments, like CLEOPATRA, where there was a large percent of patients that got trastuzumab with chemotherapy who did really well for a really long time; and, yet, we saw a 15.6 month survival benefit when we added pertuzumab. So, when you have highly effective targeted agents, I come to it from a place where you start the fulvestrant and the palbociclib. And if they have untoward toxicity, you can always stop the palbociclib. I don’t think we have any data at this point, I can’t believe I’m being more aggressive than you.

Adam M. Brufsky, MD, PhD: This is great. See the evolution. I think we’re all so excited about targeted therapies. This is tremendous.

Kimberly L. Blackwell, MD: You try it because I think we have other examples of where adding a highly effective targeted agent, even in de novo never-treated-before patients has improved outcomes. And CLEOPATRA is a good example because the majority of those women were de novo HER2-positive. They had never seen HER2-targeted therapy.

Joyce A. O’Shaughnessy, MD: That’s the survival. That’s the thing. I would be saluting if we had the year, you know what I mean? So, we’ll have to wait and see with longer follow-up.

Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD, PhD:
So, this trial was phase II. I think it did not, if I’m not mistaken, meet its primary endpoint which was overall survival. Is that correct?

Sunil Verma, MD, MSEd, FRCPC: No, they were looking at response rate.

Adam M. Brufsky, MD, PhD: Response rate. That’s right, I’m sorry. It didn’t meet that.

Sunil Verma, MD, MSEd, FRCPC: Yes. They had a qualification of response rate, but it’s hard to have a primary endpoint defined in such a manner because they had a range of response rates. Overall, 20% of patients had a response. Duration of response was good. PFS (progression-free survival) looks good. This is an active agent.

Adam M. Brufsky, MD, PhD: So, you’re the FDA. You see these data. Now, you’ve given them an accelerated designation. What do you do with it at this point in time knowing that there are other trials? And maybe, Joyce, you can summarize what those trials were…There are other abemaciclib trials now coming down the pike. There’s abemaciclib plus letrozole, and abemaciclib plus fulvestrant.

Kimberly L. Blackwell, MD: And HER2 targeted agents.

Adam M. Brufsky, MD, PhD: And abemaciclib plus HER2-targeted agent. Hopefully some of those trials will announce in the next year I’m guessing, maybe MONARCH-2 for example. So, what do you do? I’m putting you on the spot.

Sunil Verma, MD, MSEd, FRCPC: It’s a tough one.

Carlos L. Arteaga, MD: The FDA has defined the requirements to achieve breakthrough designation, and a result like this would fit that eligibility.

Adam M. Brufsky, MD, PhD: Right, and I agree with you. I’m curious as to what the other panel members think.

Sunil Verma, MD, MSEd, FRCPC: The FDA discussant at the sessions, she was excellent, and they also recognize that there is some subjectivity that goes along with this. But I think to Kim’s point, to have a targeted drug, a single agent therapeutic intervention that is active in this setting has not been shown outside of hormone receptor-positive disease and outside of chemotherapy. So, I think they’ll have to evaluate that, and evaluate the fact that it didn’t quite meet their definition of an effective response criteria. I think that’s a discussion.

Joyce A. O’Shaughnessy, MD: But clinical benefit rate is so important, and we know that from a clinical standpoint having prolonged stable disease or a response is the same thing in terms of your overall outcome. Response is not the best measure in the endocrine therapy setting. And so if we go back to the accelerated approval of capecitabine back in 1998, there was a 19% response rate. Clinical benefit rate wasn’t really on the radar screen, survival of 12.8 months. It met that unmet medical need, and I guess that’s the debatable point here. I think it’s an unmet need, and I really want the drug so I’m hoping that it will get approval.

Adam M. Brufsky, MD, PhD: I hope so, too. Apparently, they have an expanded access program that’s starting very soon anyway, but, nonetheless, hopefully it will be approved at some point.

Joyce A. O’Shaughnessy, MD: That’s good.

Kimberly L. Blackwell, MD: I think the real strength from a regulatory perspective is it’s not like this is the only study we’re going to have with this drug. We saw this with pertuzumab in particular, where larger registration randomized studies have been completed, and so they granted a conditional approval. I would hope that that would be the case here. We all know expanded access is valuable to patients, but it would be better I think just to have the drug while we’re waiting for the other studies to report out.

Adam M. Brufsky, MD, PhD: Going back, there’s a third one out now. There’s ribociclib, which actually has a whole series of trials that will announce. Any thoughts on ribociclib? Sunil?

Sunil Verma, MD, MSEd, FRCPC: The MONALEESA series of trials covers the ribociclib spectrum. MONALEESA-2 has met its primary endpoint of PFS, so this is going to be reported later this year. I think we are seeing this class effect now with palbociclib, now ribociclib being positive, and abemaciclib, which has a unique mode of action compared to the other two. So, this is an exciting time in hormone receptor-positive breast cancer. I think Kim mentioned we’re near doubling, to go from 14 months to 25 months PFS in the first-line setting. It is shifting things dramatically, and I think it really remains to be seen how we can take this and identify those patients early on to potentially potentiate this effect in the adjuvant setting, in the neoadjuvant setting. I think those are the kind of questions that we need to start discussing now.

Carlos L. Arteaga, MD: The fact that the control arm had such prolonged PFS suggests that this happened in a population that is very hormone dependent, very endocrine sensitive, and probably suggests that we should consider this in all patients in first-line in the metastatic setting and not wait.

Sunil Verma, MD, MSEd, FRCPC: What is the role of single-agent endocrine therapy now? Where does single-agent endocrine therapy?

Adam M. Brufsky, MD, PhD: Let’s get to that now. So, we have FALCON which has not—at least at the time of our discussion here—formally been announced but apparently there was a press release suggesting that it had a survival advantage as single agent.

Sunil Verma, MD, MSEd, FRCPC: PFS.

Adam M. Brufsky, MD, PhD: PFS advantage. Where do we put that now? Where do we put single-agent endocrine therapy?

Joyce A. O’Shaughnessy, MD: FALCON is the frontline study of fulvestrant versus anastrozole. It is following up on the first trial. Again, the thing about those patients—this is really the crux of the matter I think—is that they are totally endocrine therapy naïve, and that’s where I struggle. I will tell you that I agree with you, that the PALOMA-2 trial with the 14.5 months median PFS in the control arm says it’s an endocrine therapy–sensitive patient population. But, for these de novo metastatics that present with a very, very minor amount of bone disease, for example, we’ll have to wait for the FALCON actual results to see. I’m not yet convinced that every single patient who is first-line metastatic requires palbociclib. I’m one of those that still wants to see. Now, in PALOMA-1, when you looked at the de novo metastatics and the bone-onlys—bone-only disease—they got every bit as much benefit from the palbociclib. I couldn’t find a subset in that group that didn’t, including the most endocrine therapy sensitive patients. But still I have patients in the practice that have been on—we all do—first-line endocrine therapy for de novo metastatic disease for 5 plus years. There are these patients, and I think that we need to see, we have to wait for the FALCON data. We want to see some biomarker data. We want to really get deep into the clinical subsets on the PALOMA-2 data and then go from there because I think it’s still an open question.

Adam M. Brufsky, MD, PhD: Based on PALOMA-3, would you use palbociclib with fulvestrant?

Kimberly L. Blackwell, MD: Well, I would. I think Joyce and I are probably saying the same thing. I think we’ve learned from other targeted therapy experiments, like CLEOPATRA, where there was a large percent of patients that got trastuzumab with chemotherapy who did really well for a really long time; and, yet, we saw a 15.6 month survival benefit when we added pertuzumab. So, when you have highly effective targeted agents, I come to it from a place where you start the fulvestrant and the palbociclib. And if they have untoward toxicity, you can always stop the palbociclib. I don’t think we have any data at this point, I can’t believe I’m being more aggressive than you.

Adam M. Brufsky, MD, PhD: This is great. See the evolution. I think we’re all so excited about targeted therapies. This is tremendous.

Kimberly L. Blackwell, MD: You try it because I think we have other examples of where adding a highly effective targeted agent, even in de novo never-treated-before patients has improved outcomes. And CLEOPATRA is a good example because the majority of those women were de novo HER2-positive. They had never seen HER2-targeted therapy.

Joyce A. O’Shaughnessy, MD: That’s the survival. That’s the thing. I would be saluting if we had the year, you know what I mean? So, we’ll have to wait and see with longer follow-up.

Transcript Edited for Clarity
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